Featured Publications

Neuroblastoma is one of the most frequent pediatric solid tumors. Amplification of the transcription factor MYCN is the central hallmark of high-risk disease and results in excess levels of the protein in the nucleus where it can bind many thousands of regions the genome. Here we show that when amplified, oncogenic MYCN begins to invade tissue specific enhancers where it reshapes the neuroblastoma gene expression program in collaboration with tissue specific transcription factors like TWIST1. This axis of enhancer regulated genes correlates with poor survival and is dependent on tissue specific transcription factor activity creating an avenue to selectively target the activity of oncogenic MYCN.

Medulloblastoma origins (Lin et al., 2016 Nature)

In this collaboration with St. Jude's and the German cancer research center (DKFZ), we mapped active enhancer landscapes across all four known medulloblastoma subtypes. In many developmental models including embryonic stem cells, large clustered enhancer elements (super-enhancers or SEs) regulate key lineage specifying transcription factors that in turn bind and regulate other lineage transcription factors through enhancers. We hypothesized and showed that an inference of transcription factor connectivity learned through analyzing subtype specific enhancer landscapes could reveal key subtype specific lineage master regulators. We identified a subset of transcription factors (HLX, EOMES, LHX2, and LMX1A) that delineate the Group3/Group4 regulatory axis. Lineage tracing of these factors identified spatiotemporal restricted expression in the nuclear transitory zone, an assembly point for immature deep cerebellar nuclei. Deletion of LMX1A, a Group4 specific factor, in mice causes developmental defects in the developing cerebellum in this region and reductions in expression for other Group4 genes. This approach establishes a framework for the inference of tumor cell of origin mapping through the analysis of enhancer regulator landscapes.